Alzheimer's disease (AD), the most common neurodegenerative disorder, currently affects several million people in the United States. Animal models of AD provide the best hope of deciphering the course of the disease and identifying and testing potential therapeutic targets with the ultimate goal of curing the disease. Since scientific studies have revealed that AD is a complex, polygenic disorder, more than one model is required to fully understand the pathogenesis of AD and develop therapeutic approaches. A major goal of the present study is to develop such models. The study will determine if transgenic mice expressing the human apolipoprotein E variants ApoE-2, -3, or -4 and a mutant of human amyloid precursor protein, APPSWED, will develop neuropathological alterations characteristic of AD. The APPSWED mutation is associated with a form of familial AD which may be accelerated or worsened by the coexistence of the APOE-4 allele (gene, APOE; protein, ApoE). Conversely, ApoE-2 and ApoE-3 may ameliorate the development of AD-like pathology in APPSWED transgenic mice. Transgenic mice will be developed that over-express the two human genes in brain, but express no mouse ApoE or APP. At appropriate ages, the mice will be tested to determine if and when they develop pathological hallmarks of AD: memory loss, decreased brain metabolism, decreased gray matter and/or increased ventricular volume and brain histopathology such as neuritic plaques and neurofibrillary tangles. The following hypotheses will be tested: Transgenic mice expressing human apolipoprotein E4 (ApoE-4) and mutated amyloid precursor protein, APPSWED, in brain will develop an aggressive form of AD with early onset of symptoms; mice expressing the other common apolipoprotein E isoforms, ApoE-2 or ApoE-3, plus APPSWED will develop less severe forms of AD. Strengths of the study are (i) a unique and rational choice of promoters to drive expression of the transgenes, (ii) the first examination of the contribution of ApoE-4 with APPSWED in a transgenic mouse; the two proteins are expected to interact and augment initiation of AD-like pathology, (iii) the first study to compare interactions of ApoE-2, -3, and -4 with APPSWED in transgenic mice, and (iv) the effects of expression of APOE-2, -3, and -4 and APPSWED will not be complicated or attenuated by the presence of the mouse APOE or APP genes.